Chromatin and Gene Regulatory Dynamics of Optic Nerve Invasion in Retinoblastoma at Single-Cell Resolution
Zhao, Y.; Liu, P.; Hu, L.; Ke, M.; Min, N.; Zeng, Z.; Du, H.
Show abstract
Retinoblastoma (RB), the most aggressive pediatric intraocular malignancy, urgently requires mechanistic insights to overcome limitations of current clinical interventions. Through integrated single-cell multi-omics analysis, we constructed a comprehensive epigenetic-transcriptomic atlas of photoreceptor subpopulations in RB. Pseudotemporal trajectory analysis revealed the differentiation cascade from retinal progenitor cells (RPCs) to malignant cone-like tumor cells (Cone-T), orchestrated by dynamic regulation of tumor suppressors (FEZ1) and oncogenic drivers (CITED2) within the MAPK pathway. Notably, we identified three photoreceptor subtype-specific transcription factors (EBF1, SOX15, NFIL3) exhibiting concordant overexpression and chromatin accessibility. Cell-cell communication analysis uncovered PPIA-BSG ligand-receptor interactions potentially driving tumor progression, while drug screening prioritized nine therapeutic candidates targeting transitional proliferative photoreceptors (P-p). Our findings establish a mechanistic framework for photoreceptor transformation and provide actionable targets for precision therapies.
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